Methylene blue, which is also known as methylthioninium chloride or 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride, is an organic compound that corresponds to the formula below:

Methylene blue has been used as a redox indicator and dye, an optical developer in biophysical systems, in nanoporous materials as a separating material, and in photoelectrochromic imaging. Methylene blue has also been used as an antiseptic, anti-infective, as an antidote (i.e., a remedy to counteract the effects of a poison) and as a diagnostic agent. Methylene blue has found uses in many medical fields, including gynecology, neonatology, cancerology, oncology, urology, ophthalmology and gastroenterology.
In particular, methylene blue can be used to prevent or inhibit an exaggerated hymodynamic reaction (WO 2003/082296). That is, methylene blue or a related compound can be used to prevent or reverse hypotension, unstable angina, myocardial infarction or shock caused by the concomitant ingestion of a phosphodiesterase inhibitor, such as sildenafil citrate, and a NO-donor, such as L-arginine, or an organic nitrate, such as nitroglycerin.
Methylene blue has also been shown to reduce pathogenic contaminants in the blood (GB2373787). Methylene blue or derivatives thereof may also be used or incorporated in pharmaceutical compositions, medical devices, woven and non-woven fibers, dyestuffs and surface coating materials.
Methods of synthesizing the above compound require metal compounds in at least one synthetic step. For example, patent DE-1886 describes a process with oxidative coupling of N,N-dimethyl-1,4-diaminobenzene carried out with H2S and FeCl3. Fiez David et al. (“Fundamental Processes of Dye Chemistry”, Interscience, pages 308-314 (1949)) describes a process in which the thiazine ring is formed by treatment with manganese dioxide or with copper sulfate, and a treatment with zinc chloride, sodium dichromate and aluminum thiosulfate. WO 2005/054217 describes a method of preparing methylene blue derivatives with phenothiazine as starting product. Methods for preparing phenothiazine require metal reactants in which the metal atoms chelate the phenothiazine at the end of the synthesis. Therefore, methylene blue produced by this process are naturally contaminated with metal residues, as well as the organic contaminants, such as azure B, that are typically present. WO 2006/032879 describes a process for preparing methylene blue that includes three steps comprising metal compounds, for example, (1) a reduction step with iron, (2) an oxidation step with sodium dichromate, and (3) an oxidation step with copper sulfate.
Expensive purification steps are utilized to reduce the impurities, particularly metal impurities, in methylene blue and other diaminophenothiazinium type compounds. Nevertheless, these various processes produce methylene blue with metal and organic impurities. Despite asserting that metal impurities representing 10% of the maximum threshold of the European Pharmacopeia can be achieved, the examples of WO 2006/032879 demonstrates that the process described therein does not achieve this for all metals simultaneously and are not always reproducible. The European Pharmacopeia was amended in April 2006 to provide an increase in the threshold tolerances for metal impurities because methylene blue cannot be effectively produced within the previous requirements, especially at industrial amounts.
U.S. Pat. No. 8,765,942 B2 and U.S. Pat. No. 8,815,850 B2 describe a process of preparing diaminophenothiazinium compounds, for example, methylene blue that has a high degree of purity, both of which are incorporated herein by reference in their entirety. In particular, the publications describe a process which provides a highly pure, e.g., methylene blue with very low levels of metal and organic impurities that can be extrapolated to an industrial scale. However, this process results in low solubility in water of the produced ultrapure methylene blue.
Therefore, there exists a need for ultrapure methylene blue with increased solubility in water, as compared to untreated ultrapure methylene blue, and a process for the production thereof.